The D-enantiomeric peptide with the name “D3” is known from WO 02/081505 A2. It was identified by a mirror-image phage display selection against predominantly monomeric Aβ(1-42) with the plan to stabilize this by the binding and to prevent conversion thereof into toxic Aβ aggregates. Based on the current understanding, D3 preferably converts the particularly toxic Aβ oligomers into non-toxic, non-amyloidogenic and ThT-negative, amorphous aggregates. In the animal model, even with oral administration of D3 in drinking water, treated transgenic AD mice contained much fewer plaques and demonstrated significantly improved cognitive capabilities.
However, there is still no approved medicinal drug available for the causal treatment of Alzheimer's dementia (AD). Deposits of what are known as beta amyloid peptides (Aβ) in the form of plaques are typically found in the brains of AD patients post mortem. Various forms of the Aβ, for example fibrils, have therefore long been blamed for the development and progression of AD.
For some years, the small, freely diffusible Aβ oligomers in particular have been considered to be the main cause of the development and progression of AD.
Monomeric Aβ is constantly produced throughout our entire life in our body by sequential proteolysis of the precursor protein APP (amyloid precursor protein) by β and γ-secretases (Haass and Selkoe 1993) and is not toxic per se. There are even increasing suggestions that monomeric Aβ has a physiological, perhaps even neuroprotective function in the brain (Puzzo and Arancio 2013).
It is speculated whether Aβ monomers randomly amalgamate depending on their concentration (which is determined ultimately by formation and breakdown rates in the body) and thus are increasingly likely to amalgamate spontaneously to form Aβ oligomers with increasing age. Once formed, Aβ oligomers might then multiply by a prion-like mechanism and could ultimately lead to the disease.
On the basis of these considerations, the objective of causal treatment should be to prevent the formation of toxic Aβ oligomers or to completely eliminate oligomers already present and/or to prevent the prion-like multiplication thereof, moreover without reducing the Aβ monomer concentration.
There is thus currently no causally acting medicinal drug for the treatment of Alzheimer's dementia. Used medicinal drugs are at best capable of alleviating some symptoms, but cannot delay progression of the disease, let alone stop it.
There are indeed some substances available which reduce the concentration of Aβ monomers in a wide range of ways, for example by gamma-secretase modulators, Aβ-binding ligands, etc. However, since a physiological, perhaps even neuroprotective function of monomeric Aβ in the brain is postulated, on the basis of the most recent findings in relation to the mechanism of action of Alzheimer's dementia it is not considered to be a promising approach to reduce the Aβ concentration of the monomers, but instead the concentration of the Aβ oligomers.
This hypothesis has also been confirmed by the previous negative results of clinical studies (phases II and III) on humans with active substances that reduce the monomer concentration.